Different molecular mechanisms causing 9p21 deletions in acute lymphoblastic leukemia of childhood |
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Authors: | Francesca Novara Silvana Beri Maria Ester Bernardo Riccardo Bellazzi Alberto Malovini Roberto Ciccone Angela Maria Cometa Franco Locatelli Roberto Giorda Orsetta Zuffardi |
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Institution: | 1.Biologia Generale e Genetica Medica,Università degli Studi di Pavia,Pavia,Italy;2.Istituto Scientifico “Eugenio Medea”,Bosisio Parini,Italy;3.Oncoematologia Pediatrica, Fondazione IRCCS Policlinico San Matteo,Università degli Studi di Pavia,Pavia,Italy;4.Dipartmento di Informatica e Sistemistica,Università degli Studi di Pavia,Pavia,Italy;5.Fondazione IRCCS Policlinico San Matteo,Pavia,Italy |
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Abstract: | Deletion of chromosome 9p21 is a crucial event for the development of several cancers including acute lymphoblastic leukemia
(ALL). Double strand breaks (DSBs) triggering 9p21 deletions in ALL have been reported to occur at a few defined sites by
illegitimate action of the V(D)J recombination activating protein complex. We have cloned 23 breakpoint junctions for a total
of 46 breakpoints in 17 childhood ALL (9 B- and 8 T-lineages) showing different size deletions at one or both homologous chromosomes
9 to investigate which particular sequences make the region susceptible to interstitial deletion. We found that half of 9p21
deletion breakpoints were mediated by ectopic V(D)J recombination mechanisms whereas the remaining half were associated to
repeated sequences, including some with potential for non-B DNA structure formation. Other mechanisms, such as microhomology-mediated
repair, that are common in other cancers, play only a very minor role in ALL. Nucleotide insertions at breakpoint junctions
and microinversions flanking the breakpoints have been detected at 20/23 and 2/23 breakpoint junctions, respectively, both
in the presence of recombination signal sequence (RSS)-like sequences and of other unspecific sequences. The majority of breakpoints
were unique except for two cases, both T-ALL, showing identical deletions. Four of the 46 breakpoints coincide with those
reported in other cases, thus confirming the presence of recurrent deletion hotspots. Among the six cases with heterozygous
9p deletions, we found that the remaining CDKN2A and CDKN2B alleles were hypermethylated at CpG islands. |
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